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Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer (NESCIO)

Primary Purpose

Renal Cell Carcinoma

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Neoadjuvant nivolumab
Neoadjuvant ipilimumab
Neoadjuvant relatlimab
Sponsored by
The Netherlands Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring Resectable renal cell carcinoma, Checkpoint inhibition, Immunotherapy, PD-1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, Nivolumab, Ipilimumab, Relatlimab, Neoadjuvant, NESCIO, M21NSC, Checkpoint blockade

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adults at least 18 years of age;
  • World Health Organization (WHO) Performance Status 0 or 1;
  • Histologically confirmed resectable clear cell RCC (measurable according to RECIST 1.1), that can be biopsied, and no history of distant metastases;
  • Intermediate to high risk will be based on clinical TNM and biopsy nuclear grade. These are:

    1. cT1b-cT2a grade 4 cN0 cM0
    2. cT2b grade 3 cN0 cM0
    3. cT3 any grade cN0 cM0
    4. cT4 any grade cN0 cM0
    5. cT any cN1 (fully resectable) cM0
  • No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years;
  • Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse;
  • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1, or LAG-3;
  • No immunosuppressive medications within 2 weeks prior start immunotherapy;
  • Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN, normal CK and Troponin T, normal LDH;
  • Women of childbearing potential must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug;
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment;
  • Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception;
  • Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

  • Distantly metastasized RCC;
  • Brain metastases (based on symptoms);
  • Non-clear cell RCC;
  • No measurable lesion according to RECIST 1.1;
  • Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy;
  • Prior CTLA-4 or PD-1/PD-L1 or LAG-3 targeting immunotherapy;
  • Radiotherapy prior or post-surgery;
  • Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate;
  • Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
  • Allergies and Adverse Drug Reactions (like mastocytosis);
  • History of severe hypersensitivity reaction to any monoclonal antibody;
  • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug(s) hazardous or obscure the interpretation of toxicity or adverse events;
  • Pregnant or nursing;
  • Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
  • Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion.

Relatlimab-specific exclusion Criteria:

  • Participants with history of myocarditis, regardless of etiology;
  • Troponin T (TnT) > 2 × institutional ULN. Participants with TnT levels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hours are ≤ 1 ULN. If TnT levels are between >1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the BMS Medical Monitor or designee.
  • Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to start of study treatment.

Sites / Locations

  • Netherlands Cancer InstituteRecruiting
  • Royal Free London NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

A: Neoadjuvant nivolumab

B: Neoadjuvant nivolumab + ipilimumab

C: Neoadjuvant nivolumab + relatlimab

Arm Description

Neoadjuvant 2 cycles of nivolumab 360mg every 3 weeks

Neoadjuvant 2 cycles of nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks

Neoadjuvant 2 cycles of nivolumab 360mg + relatlimab 360mg every 3 weeks

Outcomes

Primary Outcome Measures

Pathologic response rate
Pathologic response rate is defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)

Secondary Outcome Measures

Safety, measured by the frequency of immune-related adverse events leading to postponing of surgery for >2 weeks
Objective response rate
ORR is defined as the proportion of patients demonstrating a complete or partial response according to RECIST 1.1
Recurrence Free Survival (RFS)
RFS is defined as the time from randomization to recurrence or death from any cause, whichever occurs first. Subjects last known to be alive, who have not experience recurrence, will be censored.
Event-free Survival (EFS)
EFS is defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever occurs first. Subjects who are event-free at the end of follow-up will be censored.
Rate of distant metastases
The proportion of patients starting treatment who experience distant metastases during follow-up.
Rate of local recurrences
The proportion of patients starting treatment who experience a local recurrence during follow-up.
Surgical morbidity following neoadjuvant immunotherapy
Surgical complication rates according to Clavien-Dindo classification
Description of associations of TMB, fs/INDELs, HERVE-E, RNA tumor/immune signatures, and surface marker expression with tumor immune infiltrates and response
Cell free methylated DNA profiles following neoadjuvant immunotherapy between baseline and surgery
Collection of fresh tumor tissue for investigating TIL, scRNA and TCRseq

Full Information

First Posted
November 25, 2021
Last Updated
May 3, 2022
Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT05148546
Brief Title
Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer
Acronym
NESCIO
Official Title
Prospective, Randomized, Neoadjuvant Phase II Study With Combination Immuno-oncology in Primary Clear Cell Renal Cancer at Risk for Recurrence or Distant Metastases (NESCIO-trial)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 28, 2022 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The NESCIO-trial is a multicenter, randomized, open-label, three-arm phase II trial investigating different combinations of neoadjuvant immunotherapy in patients with primary, resectable, intermediate to high-risk, clear-cell renal cell carcinoma. In this trial patients will be randomized 1:1:1 to receive either 2 cycles of nivolumab 360mg every 3 weeks (arm A), 2 cycles of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks (arm B) or 2 cycles of relatlimab 360mg + nivolumab 360mg every 3 weeks (arm C), prior to surgery at week 7. After 42 patients (14 per arm) have been recruited, an interim analysis will be performed to evaluate the observed efficacy and toxicity within each arm and either allow for early discontinuation of the treatment or continuing recruitment for the second stage. As the primary endpoint, the pathological response (decrease in tumor) will be evaluated. If at most one pathologic response in the primary tumor is observed, the treatment arm will be closed for insufficient activity on the primary tumor. If at least 2 pathologic responses are observed, 9 additional patients will be included to a total of 23 patients per cohort. A maximum of 69 patients will be recruited for this study. Follow up will start at week 12 with a CT-scan according to the national/center's standard. Patients will be evaluated every 3 months by physical examination and lab testing for up to two years, thereafter according to institutional guidelines up to 5 years following surgery.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma
Keywords
Resectable renal cell carcinoma, Checkpoint inhibition, Immunotherapy, PD-1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, Nivolumab, Ipilimumab, Relatlimab, Neoadjuvant, NESCIO, M21NSC, Checkpoint blockade

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Open-label three-arm randomized phase II trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
69 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A: Neoadjuvant nivolumab
Arm Type
Experimental
Arm Description
Neoadjuvant 2 cycles of nivolumab 360mg every 3 weeks
Arm Title
B: Neoadjuvant nivolumab + ipilimumab
Arm Type
Experimental
Arm Description
Neoadjuvant 2 cycles of nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks
Arm Title
C: Neoadjuvant nivolumab + relatlimab
Arm Type
Experimental
Arm Description
Neoadjuvant 2 cycles of nivolumab 360mg + relatlimab 360mg every 3 weeks
Intervention Type
Drug
Intervention Name(s)
Neoadjuvant nivolumab
Other Intervention Name(s)
Opdivo
Intervention Description
Patients will receive 2 cycles of nivolumab 360mg (arm A and C) or 3mg/kg (arm B) every 3 weeks followed by a nephrectomy.
Intervention Type
Drug
Intervention Name(s)
Neoadjuvant ipilimumab
Other Intervention Name(s)
Yervoy
Intervention Description
Patients will receive 2 cycles of ipilimumab 1mg/kg every 3 weeks followed by a nephrectomy.
Intervention Type
Drug
Intervention Name(s)
Neoadjuvant relatlimab
Intervention Description
Patients will receive 2 cycles of relatlimab 360mg every 3 weeks followed by a nephrectomy.
Primary Outcome Measure Information:
Title
Pathologic response rate
Description
Pathologic response rate is defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)
Time Frame
At 6 weeks
Secondary Outcome Measure Information:
Title
Safety, measured by the frequency of immune-related adverse events leading to postponing of surgery for >2 weeks
Time Frame
At 8 weeks
Title
Objective response rate
Description
ORR is defined as the proportion of patients demonstrating a complete or partial response according to RECIST 1.1
Time Frame
At 6 weeks
Title
Recurrence Free Survival (RFS)
Description
RFS is defined as the time from randomization to recurrence or death from any cause, whichever occurs first. Subjects last known to be alive, who have not experience recurrence, will be censored.
Time Frame
Up to 5 years after start of treatment
Title
Event-free Survival (EFS)
Description
EFS is defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever occurs first. Subjects who are event-free at the end of follow-up will be censored.
Time Frame
Up to 5 years after start of treatment
Title
Rate of distant metastases
Description
The proportion of patients starting treatment who experience distant metastases during follow-up.
Time Frame
Up to 5 years after start of treatment
Title
Rate of local recurrences
Description
The proportion of patients starting treatment who experience a local recurrence during follow-up.
Time Frame
Up to 5 years after start of treatment
Title
Surgical morbidity following neoadjuvant immunotherapy
Description
Surgical complication rates according to Clavien-Dindo classification
Time Frame
Up to 1 year after start of treatment
Title
Description of associations of TMB, fs/INDELs, HERVE-E, RNA tumor/immune signatures, and surface marker expression with tumor immune infiltrates and response
Time Frame
Up to 5 years after start of treatment
Title
Cell free methylated DNA profiles following neoadjuvant immunotherapy between baseline and surgery
Time Frame
At 6 weeks
Title
Collection of fresh tumor tissue for investigating TIL, scRNA and TCRseq
Time Frame
At 6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adults at least 18 years of age; World Health Organization (WHO) Performance Status 0 or 1; Histologically confirmed resectable clear cell RCC (measurable according to RECIST 1.1), that can be biopsied, and no history of distant metastases; Intermediate to high risk will be based on clinical TNM and biopsy nuclear grade. These are: cT1b-cT2a grade 4 cN0 cM0 cT2b grade 3 cN0 cM0 cT3 any grade cN0 cM0 cT4 any grade cN0 cM0 cT any cN1 (fully resectable) cM0 No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years; Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse; No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1, or LAG-3; No immunosuppressive medications within 2 weeks prior start immunotherapy; Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN, normal CK and Troponin T, normal LDH; Women of childbearing potential must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug; Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment; Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception; Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document. Exclusion Criteria: Distantly metastasized RCC; Brain metastases (based on symptoms); Non-clear cell RCC; No measurable lesion according to RECIST 1.1; Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy; Prior CTLA-4 or PD-1/PD-L1 or LAG-3 targeting immunotherapy; Radiotherapy prior or post-surgery; Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate; Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); Allergies and Adverse Drug Reactions (like mastocytosis); History of severe hypersensitivity reaction to any monoclonal antibody; Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug(s) hazardous or obscure the interpretation of toxicity or adverse events; Pregnant or nursing; Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion. Relatlimab-specific exclusion Criteria: Participants with history of myocarditis, regardless of etiology; Troponin T (TnT) > 2 × institutional ULN. Participants with TnT levels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hours are ≤ 1 ULN. If TnT levels are between >1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the BMS Medical Monitor or designee. Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to start of study treatment.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
John Haanen, Prof
Phone
+31205129111
Email
j.haanen@nki.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Femke Burgers, MD
Phone
+31205129111
Email
f.burgers@nki.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Haanen, Prof
Organizational Affiliation
Medical oncologist/researcher
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Axel Bex, Prof
Organizational Affiliation
Urologist/researcher
Official's Role
Principal Investigator
Facility Information:
Facility Name
Netherlands Cancer Institute
City
Amsterdam
State/Province
NH
ZIP/Postal Code
1066CX
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Haanen, Prof
Phone
+31205129111
Email
j.haanen@nki.nl
First Name & Middle Initial & Last Name & Degree
Femke Burgers, MD
Phone
+31205129111
Email
f.burgers@nki.nl
Facility Name
Royal Free London NHS Foundation Trust
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Axel Bex, Prof
Phone
+442077940500
Email
a.bex@nki.nl

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer

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